1. Field of the Invention
The present invention is directed to a method of immunizing mammals against parasitic infections. More specifically, the invention is directed to a method of immunizing mammals using an implanted capsule containing antigenic unicellular parasites, parasite larvae or cysts.
2. Discussion of the Background
Mammalian parasites present a health hazard to both animals and humans throughout the world. In the United States, parasitic infections of livestock present potential health hazards in the food supply. Improper handling, storage, processing and distribution operations in the food industry can result in opportunities for contamination with both spore and vegetative forms of parasites, ultimately presenting a health hazard to the human consumer. Control of parasitic infections in livestock is essential to maintaining a safe and healthy food supply and optimizing food resources.
Parasitic infections of domesticated animals result in substantial veterinary expense worldwide and in potential health hazards to the animal owner. For example, cats infected with toxoplasmosis present a serious health hazard to a developing fetus. Infection of the mother during pregnancy may result in severe central nervous system damage to the fetus.
In many parts of the world, protozoan parasitic diseases such as giardiasis, leishmaniasis, trypanosomiasis, malaria and amebic dysentery are endemic. These diseases present a constant health hazard to human travelers. Additional hazards are posed by common helminthic parasites.
Parasitic disease is also a large problem in military operations. Many parasitic worms and protozoa are endemic in tropical and subtropical parts of the world. Military personnel and animals that have lived in temperate climates are susceptible to attack by the infectious forms of parasites. In many parts of the world traditional control measures, especially control of vector populations with insecticides, are losing efficacy. Parasitic infections can cause severe morbidity and even death.
Over two billion people worldwide are infected with some kind of parasite. Hundreds of millions of humans have seriously impaired health due to parasitic infections. An estimated 200 million cases of schistosomiasis, 150 million cases of malaria, and 90 million cases of filarial worm infections are found in the tropical world. Parasites cause up to $1 billion loss in economic animals and about one half of the common problems in companion animals. Travel and migration are accelerating the spread of parasites and parasitic disease. These health hazards can be substantially reduced and possibly eliminated by the development of a safe and effective method of immunization against parasitic organisms.
The technology for immunizing against parasitic diseases is largely unknown. Attempts have been made to study the response of an animal to parasite implants, however. These studies involve isolation of the parasites from the host mammals immune system to determine the effect on the implant.
U.S. Pat. No. 3,629,390 describes an early attempt to provide controlled release of a bio-affecting preparation for avian applications in which a bioaffecting compound is formulated into particles of a solid matrix material which are gradually released subject to the grinding and abrading action occurring in the avian gizzard. Early attempts to enhance biocompatibility of biological materials in a mammalian host are described in U.S. Pat. No. 3,682,776 which teaches the treatment of transplant tissues with a protease inhibitor to prevent host rejection of the transplant and by U.S. Pat. No. 4,120,649 which teaches the treatment of transplant tissues with glutaraldehyde, a bifunctional cross-linking reagent, to provide a new contact surface in the transplant which is more favorably accepted by the host. These latter methods are not actual immunoisolation of the transplanted tissue, but rather surface modification to prevent tissue rejection.
Immunoisolation has been achieved with the use of implantable diffusion chambers which employ a microporous physical barrier separating the foreign cells or tissue from host immunological cells. Diffusion chambers are generally constructed from plastic rings or cylinders to which semipermeable membranes have been firmly attached. Diffusion chambers are relatively large having cross-sections ranging from approximately 10-20 mm. Materials for constructing diffusion chambers are commercially available.
Implantable diffusion chambers utilize semipermeable membranes which allow the selective diffusion of molecules in and out of the diffusion chamber but prevent the movement of cells, into the diffusion chamber. Much research has been focused on the use of diffusion chambers for treatment of diabetes. Using such methods, pancreatic islet cells are enclosed in a diffusion chamber which is then implanted in a diabetic mammal. Insulin diffuses through the semiporous diffusion chamber membrane and can ameliorate diabetic conditions for limited periods of time. See, for example, G.F. Klomp et al, Trans. Am. Soc. Artif. Intern. Organs, (1979), 25:74-76. Diffusion chambers in the form of artificial capillary units for use in treating diabetes have been described (A.M. Sun et al, Diabetes, (1977), 12:1136-1139). Diffusion chambers have also been used to study bacterial pathogenesis, e.g., Bordetella pertussis pathogenesis (K.D. Coleman and L.H. Wetterlow, Journal of Infectious Diseases, (1986), 154:33-39).
Diffusion chambers have been used to immunoisolate parasitic tissue or infective larvae in studies relating to the immune response of a host to parasitic infection. For example, diffusion chambers have been used to study response to Schistosoma mansoni (A.I. Kassis et al, Journal of Immunology, (1979), 123:1659-1662); Dipetalonema viteae (M. Tanner et al, Transactions of the Royal Society of Tropical Medicine and Hygiene, (1981), 75:173-174) and D. Abraham et al, Immunology, (1986), 57:165-169); Brugia pahangi (R. Chandrashekar et al, Parasite Immunology, (1985), 7:633-641 and J.P. Court, Tropenmed. Parasit., (1982), 33:83-86); Onchocerca volvulus (G. Strote, Trop. Med. Parasit., (1985), 36:120-122); Trypanosoma Cruzi (A. Sher et al, J. Protozool., (1983), 30:278-283); Ascaris suum (C.A. Crandall and V.M. Arean, Journal of Parasitology, (1964), 50:685-688); and Dirofilaria immitis (D. Abraham et al, J. Parasit., (1988), 74:275-282 and C.J. Delves, R.E. Howells, Trop. Med. Parasit., (1985), 36:29-31). None of these studies have attempted to immunize an animal against parasitic infection.
The use of diffusion chambers for encapsulation of tissues, cells or parasitic larvae is limited by the tendency of these relatively large chambers to become covered by a thick fibrous layer. Implantation of diffusion chambers, therefore, results in isolation of the diffusion chamber by the host immune system and provides limited utility in establishing immunity against parasitic infections. The use of diffusion chambers to provide immunity against parasitic infections is therefore unsuitable.
An alternative to the use of diffusion chambers is the microencapsulation of antigenic material in a semipermeable membrane. Microencapsulation differs from the use of diffusion chambers in several aspects. In microencapsulation processes, biological tissue or cells are encapsulated in a semipermeable membrane resulting in a product which is substantially smaller than a diffusion chamber. Microencapsulated tissue is not, in general, bioisolated by the host immune system in the same manner as diffusion chambers. As with diffusion chambers, substantial research in the field of microencapsulation has been directed to the treatment of diabetes and involves the encapsulation of pancreatic islet tissue (G.F. Klomp et al, loc. cit.; Tze et al, Transplantation Proceedings, (1982), 14:714-723; Leung et al, Artificial Organs, (1983), 7:208-212; Sun et al, Diabetes, (1977), 26:1136-1139; Lim et al, Science, (1980), 210:908-910; and U.S. Pat. No. 4,806,355). Microencapsulation of other mammalian tissues and cells are described, for example, in Lamberti et al, Abstract paper Amer. Chem. Soc., (1983), 85:162; Lamberti et al, Artificial Organs, (1984), 8:112; Lim and Moss, Journal of Pharm. Sciences, (1981), 70:351-354; Canadian patent 1,215,922 and U.S. Pat. No. 4,353,888.
The technology of microencapsulation as applied to transplant tissues and cells has been well described and elucidated. See for example U.S. Pat. Nos. 4,696,286; 4,407,957; 4,409,331; 4,391,909; 4,352,883 and 4,251,387. Microencapsulation techniques have been utilized to encapsulate drugs, mammalian tissues, isolated cells and bacterial cells.
The use of liposomes, i.e., vessels made of phospholipids, has been proposed for both drug delivery and the delivery of vaccines. Alving et al describe the effectiveness of liposomes as potential carriers of vaccines (C. Alving, et al, Vaccine, (1986), 4:166). The liposomes could carry cholera toxin, reducing toxicity while enhancing antigenicity. Human malaria sporozoite antigen, itself non-immunogenic, was found to induce antibodies when carried by liposomes.
The disadvantage of liposomes is that the particles are prone to being phagocytosed by cells of the reticular endothelial system, thereby destroying the source of antigenic material and preventing release of antigens. Further research is necessary to reduce the effect of phagocytosis sufficiently to allow the use of liposomes as slow release agents.
Implantation of diffusion chambers results in the partial biological isolation of the diffusion chambers by the immune system of the host mammal. Liposomes are rapidly phagocytosed by host immune cells. Accordingly, improved immunological methods and implants are desired to provide the required immunoisolation and establish the immunity necessary to protect against parasitic diseases in animals.